Despite remarkable advances in medical research and treatments during the 20th century, infection- associated cancers remain among the leading causes of death worldwide. Among a wide variety of factors that enable pathogens to invade host populations and cause diseases, host characteristics such as immunosuppression are the foremost contributing factors. Specifically, those with HIV/AIDS have an increased incidence of Kaposi's Sarcoma (KS) relative to the general population, highlighting how important host immunity is in controlling Kaposi's sarcoma-associated herpesvirus (KSHV) that is one of seven human oncoviruses. In order to improve our ability to respond more effectively to KS in immunosuppressed patients, we should thus improve our understanding of how hosts and KS-causing pathogen combat each other and how KS-causing pathogen operates in the immune compromised hosts. Specifically, understanding how KSHV gene products contribute to the establishment of persistent infection and pathogenesis requires a reverse genetics approach for the viral genetic manipulation, in vitro and in vivo assay systems for viral oncogenesis, and an animal model for in vivo viral persistence under active host immune conditions. Thus, our achievements in the following ways will provide biologically relevant settings for the study of in vivo KSHV persistence and pathogenesis: understanding the viral evasion of host immunity and the viral strategy of cell growth transformation and developing the infectious KSHV BAC clone and the humanized mouse and primate models.